INTRODUCTION — Caroli disease is a congenital disorder characterized by multifocal, segmental dilatation of large intrahepatic bile ducts [1,2]. The condition is usually associated with renal cystic disease of varying severity. Caroli initially described two variants, which has led to some confusion in terminology.

●Caroli disease is the less common form and is characterized by bile ductular ectasia without other apparent hepatic abnormalities.

●The more common variant is Caroli syndrome in which bile duct dilatation is associated with congenital hepatic fibrosis [3].

Caroli disease and syndrome have been described in the same family. Most cases are transmitted in an autosomal recessive fashion and are associated with autosomal recessive polycystic kidney disease (ARPKD). There have been rare cases occurring with autosomal dominant polycystic kidney disease [4]. In addition, Caroli disease and syndrome has also been associated with other hepatorenal fibrocystic diseases including Nephronophthisis 13, Meckel–Gruber syndrome, COACH syndrome, Joubert syndrome and related disorders, Bardet–Biedl syndrome, and oral–facial–digital syndrome.

PATHOGENESIS — The molecular pathogenesis of Caroli disease and syndrome is incompletely understood. The gene underlying autosomal recessive polycystic kidney disease (ARPKD) had been mapped to chromosome 6 (6p21-p12). The affected gene (called PKHD1 for polycystic kidney and hepatic disease 1) encodes for a large protein (4074 amino acids), which has been called fibrocystin to reflect the main structural abnormalities in liver and kidney [5]. The protein shares structural features with the hepatocyte growth factor receptor, localizes to cilia, and appears to belong to a superfamily of proteins that involve numerous cellular functions including regulation of cell proliferation, differentiation, cell adhesion and repulsion, tubulogenesis, cell polarity, and cell matrix interactions [6-8]. It does not share any homology with the proteins responsible for autosomal dominant polycystic kidney disease (ADPKD). PKHD1 is expressed primarily in the kidneys with lower levels in liver, pancreas, and lungs, a pattern consistent with phenotype of the disease, which primarily affects the liver and kidneys. The genetic basis for the difference in Caroli disease and syndrome has not been defined.

Mutations in either of two different genes (PKD1 or PKD2) give rise to ADPKD, which, as mentioned above, has been associated with Caroli disease in rare instances. The protein products of the PKD genes (polycystin-1 and polycystin-2) are thought to interact as part of a multiprotein membrane-spanning complex involved in cell-cell or cell-matrix interactions [9,10]. Polycystin-1 is expressed in the fetal kidney and liver including the biliary system and is likely involved in the embryogenesis of these organs.

Nephronophthisis 13, which can be accompanied by Caroli syndrome or disease, is associated with mutations in the WDR19 gene, which encodes for a protein required for retrograde ciliary transport [11].

The proteins that are defective in most of the fibrocystic diseases of the liver and kidney, including ARPKD and ADPKD, are expressed on the primary cilia and centrosome complex of renal tubule cells and cholangiocytes [12]. Primary cilia are non-motile, microtubule-based organelles that are found on the luminal surface of many differentiated epithelial cells. They sense mechanical, chemical, and osmotic stimuli associated with luminal fluid flow and transmit these signals to a variety of intracellular signal transduction pathways, involving mediators such as intracellular calcium and cyclic AMP. Urine and bile composition is thought to be modified as a result of cilia-based signaling. Ciliary function is also essential for normal development of the liver and biliary system through effects on cell proliferation and maintenance of planar cell polarity. These properties are severely disrupted in ARPKD and ADPKD.

PATHOLOGY — In both Caroli disease and Caroli syndrome, the biliary abnormality consists of segmental, saccular dilatations of the large intrahepatic bile ducts [13,14]. While the segmental bile ducts are predominantly involved, the dilated portions are in continuity with the rest of the biliary tract. The disease may be limited to one lobe of the liver, most commonly the left lobe.

The dilated ducts are lined by biliary epithelium that may be hyperplastic, ulcerated and surrounded by a macrophage-dominated immune infiltrate. In Caroli syndrome, the liver also shows features of congenital hepatic fibrosis, including fibrosis and enlargement of portal tracts, which often contain variable numbers of abnormally shaped bile ducts and hypoplastic portal vein branches. The pathogenesis of the intrahepatic ductal dilatation and hepatic fibrosis appears to be related to an arrest or derangement in remodeling of the ductal plate of the larger intrahepatic bile ducts during development [15]. In congenital hepatic fibrosis, a genetically determined dysfunction of cholangiocyte homeostasis promotes the secretion of chemokines able to recruit macrophages that orchestrate a pro-fibrotic tissue response [16]. One group proposed that the genetic abnormality leading to abnormal remodeling of the ductal plate can exert its influence during an early period of bile duct embryogenesis, leading to Caroli disease, or later on producing abnormalities in the peripheral biliary ramifications (the intralobular bile ducts) leading to Caroli syndrome [13].

CLINICAL MANIFESTATIONS — The clinical manifestations of Caroli syndrome are related both to the biliary abnormalities and portal hypertension from congenital hepatic fibrosis [14]. There are several modes of presentation depending on the age of onset and the predominance of hepatic or renal involvement. Autosomal recessive polycystic kidney disease (ARPKD) frequently presents in neonates and can even be detected in utero, although age at presentation is highly variable since presenting symptoms have been reported in adults (portal hypertension or cholangitis) or neonates with renal disease or cholestasis. (See "Autosomal recessive polycystic kidney disease in children" and "Approach to evaluation of cholestasis in neonates and young infants".)

In both Caroli disease and Caroli syndrome, the saccular or fusiform dilatation of bile ducts predisposes to stagnation of bile leading to the formation of biliary sludge and intraductal lithiasis. Bacterial cholangitis occurs frequently and may be complicated by septicemia and hepatic abscess formation [2]. (See "Acute cholangitis: Clinical manifestations, diagnosis, and management".) Secondary biliary cirrhosis can occur due to biliary obstruction.

Patients with Caroli syndrome can present with portal hypertension and its sequelae, such as ascites and esophageal variceal hemorrhage. Other patients present only with intermittent abdominal pain. Pruritus and hepatomegaly are common. Children with Caroli syndrome usually have an earlier onset of symptoms and a more rapidly progressive disease because of the combined effects of cholangitis and portal hypertension.

On physical examination, the liver is frequently enlarged and the spleen becomes palpable as portal hypertension develops. Patients with renal involvement may also have enlarged kidneys, which may be palpable. Laboratory studies typically show an elevation of serum alkaline phosphatase, direct bilirubin, and a leukocytosis with a predominance of neutrophils. Hepatic synthetic function is well preserved initially, but may be affected by progressive liver damage due to recurrent cholangitis and biliary obstruction. Coagulopathy from vitamin K malabsorption may occur in cholestatic patients. Children presenting with ARPKD should be followed closely for evidence of liver disease. Juvenile nephronophthisis and medullary cystic disease have been observed, although they are probably rare [17].

DIAGNOSIS — The diagnosis of Caroli disease and Caroli syndrome is established by imaging studies that demonstrate bile duct ectasia and irregular, cystic dilation of the large proximal intrahepatic bile ducts with a normal common bile duct [18]. These findings can be seen readily with ultrasonography, endoscopic retrograde cholangiopancreatography, and magnetic resonance cholangiography (picture 1) [19,20]. The so-called "central dot sign," defined as a small foci of strong contrast enhancement within dilated intrahepatic ducts, is often found on computed tomography scan or magnetic resonance imaging [21]. Imaging studies can also demonstrate the renal features of autosomal recessive polycystic kidney disease. Prenatal diagnosis of Caroli disease associated with autosomal recessive polycystic kidney disease has been made by 3-D ultrasound and magnetic resonance imaging [22].

A liver biopsy is rarely required to make a diagnosis. When obtained in Caroli syndrome, it typically shows broad bands of mature fibrosis tissue and distorted bile duct structures characteristic of congenital hepatic fibrosis. There may also be hypoplasia of the portal vein branches. An acute and chronic inflammatory cell infiltrate may be seen around the dilated bile ducts. In Caroli disease, there is only ectasia of the larger intrahepatic ducts. Liver biopsy may show features of cholangitis.

Differential diagnosis — There may be some confusion with extrahepatic choledochal cysts, one form of which can extend into the intrahepatic bile ducts (type V choledochal cysts) (figure 1). However, choledochal cysts are not a form of Caroli disease. Rare cases of Caroli syndrome have been associated with autosomal dominant polycystic kidney disease in which irregularly sized cysts are distributed throughout the kidney with frequent progression of the cysts with age [4].

TREATMENT — Treatment is largely supportive and should be individualized [23,24]:

●Cholangitis and sepsis should be treated with appropriate antibiotics and biliary stone extraction whenever feasible. Because of bile stasis and the presence of intrahepatic lithiasis, infection may be particularly difficult to eradicate and can be associated with progressive deterioration of liver function. Patients may require prolonged courses of antibiotics.

●Patients with chronic cholestasis should receive supplements of fat-soluble vitamins.

●Patients who have developed esophageal varices should receive prophylaxis with a nonselective beta blocker. A selective shunting procedure can provide relief from portal hypertension since liver function may be well preserved. (See "Primary and pre-primary prophylaxis against variceal hemorrhage in patients with cirrhosis".)

●Otherwise unexplained clinical deterioration or the appearance of a new biliary stricture should raise concern that cholangiocarcinoma has developed. Whether patients should undergo surveillance for cholangiocarcinoma is unclear. (See "Clinical manifestations and diagnosis of cholangiocarcinoma".)

Endoscopic sphincterotomy and stone extraction can be used to remove common duct stones [25]. In contrast, the extraction of intrahepatic stones is far more difficult. In one study, endoscopic sphincterotomy followed by either extracorporeal shock-wave lithotripsy or intraductal electrohydraulic lithotripsy was successful in clearing intrahepatic stones in four of six adults and partially in another two [26]. Per oral cholangioscopy using a mother-daughter endoscope system was successful in 23 of 36 patients (60 percent) in another report of patients with hepatolithiasis [27]. Long-term follow-up of these patients suggested that stone clearance can be durable. Laser lithotripsy appears to have a more limited role for intrahepatic stones and is not widely available. (See "Cholangioscopy and pancreatoscopy" and "Laser lithotripsy for the treatment of bile duct stones".)

Dissolution therapy using synthetic bile salts has also been described. In one of the largest series, for example, ursodeoxycholic acid (10 to 20 mg/kg per day for a mean of 48 months) was associated with complete dissolution of intrahepatic stones in three patients and partial dissolution in another nine [28]. Ursodeoxycholic acid works probably by increasing bile flow and decreasing bile stasis rather than by dissolving the stones, since most stones are pigmented. (See "Overview of nonsurgical management of gallbladder stones".)

Removal of intrahepatic stones by surgery is usually not feasible [29]. However, partial hepatectomy may be curative in rare patients in whom the disease is confined to a single lobe of the liver [30-33]. There was no operative mortality in a retrospective, multicenter report of one of the largest series of liver resection for Caroli disease or Caroli syndrome (n = 111, with approximately 90 percent involving the left lobe of the liver). The 5- and 10-year survival rates for patients undergoing the surgery were 89 and 82 percent, respectively [34].

Patients who have recurrent bouts of biliary infection, particularly those who also have complications related to portal hypertension, may require liver transplantation [31,35-37]. A study of 140 patients with Caroli disease or syndrome based on United Network for Organ Sharing data transplanted between 1987 and 2011 showed excellent patient and graft survival that was comparable to or better than that of patients transplanted for other diseases [37].

PROGNOSIS — The prognosis is variable depending upon the severity of disease and the presence of coexisting renal dysfunction. Recurrent infections and other complications related to biliary lithiasis can be associated with significant morbidity. As mentioned above, liver transplantation may be the only option in patients with refractory disease. The risk of cholangiocarcinoma is increased (up to 7 percent), probably due to the significant bile stasis and the presence of high concentrations of unconjugated secondary bile salts. Amyloidosis has also been described due to the inflammation from chronic or recurrent cholangitis [38]. (See "Epidemiology, pathogenesis, and classification of cholangiocarcinoma".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatic and biliary cysts".)

SUMMARY AND RECOMMENDATIONS

●Caroli disease is characterized by bile ductular ectasia without other apparent hepatic abnormalities. By contrast, Caroli syndrome is characterized by bile duct dilatation associated with congenital hepatic fibrosis. Caroli syndrome is more common that Caroli disease.

●The molecular pathogenesis of Caroli disease and syndrome is incompletely understood. Most cases are transmitted in an autosomal recessive fashion and are associated with autosomal recessive polycystic kidney disease. (See 'Pathogenesis' above.)

●The clinical manifestations of Caroli syndrome are related both to the biliary abnormalities and portal hypertension from congenital hepatic fibrosis. There are several modes of presentation depending on the age of onset and the predominance of hepatic or renal involvement. Bacterial cholangitis occurs frequently and may be complicated by septicemia and hepatic abscess formation. Secondary biliary cirrhosis can occur due to biliary obstruction. (See 'Clinical manifestations' above.)

●The diagnosis of Caroli disease and Caroli syndrome is established by imaging studies that demonstrate bile duct ectasia and irregular, cystic dilation of the large proximal intrahepatic bile ducts with a normal common bile duct. These findings can be seen readily with ultrasonography, endoscopic retrograde cholangiopancreatography, and magnetic resonance cholangiography (picture 1). (See 'Diagnosis' above.)

●Treatment is largely supportive and should be individualized. (See 'Treatment' above.)

●The prognosis is variable depending upon the severity of disease and the presence of coexisting renal dysfunction. (See 'Prognosis' above.)